CN115043848A - Preparation method of S- (+) -etodolac methyl ester - Google Patents

Preparation method of S- (+) -etodolac methyl ester Download PDF

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CN115043848A
CN115043848A CN202210197229.3A CN202210197229A CN115043848A CN 115043848 A CN115043848 A CN 115043848A CN 202210197229 A CN202210197229 A CN 202210197229A CN 115043848 A CN115043848 A CN 115043848A
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reaction
methyl
catalyst
filtrate
etodolac
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孙晓雷
祝士国
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Shandong New Time Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers

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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of S- (+) -etodolac methyl ester. The method takes a compound I as a starting material, and prepares a single isomer S- (+) -etodolac methyl ester with 3-oxo methyl valerate under the action of a chiral catalyst, wherein the reaction formula is shown as follows. Compared with the method for preparing S- (+) -methyl etodolate by adopting a chiral resolution technology in the prior art, the method can prepare the S- (+) -methyl etodolate with high yield and high purity, and avoids the generation of enantiomers, so that the utilization rate of raw materials is improved, and the production cost is reduced.

Description

Preparation method of S- (+) -etodolac methyl ester
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of S- (+) -etodolac methyl ester.
Background
Etodolac (Etodolac) is a potent nonsteroidal anti-inflammatory analgesic, is used for treating rheumatoid arthritis, osteoarthritis and other symptoms, has the characteristics of good tolerance, light toxic and side effects, strong analgesic effect and the like, has few gastrointestinal adverse reactions, and is particularly suitable for elderly patients. The drug is developed by AHP Wyeth-Ayesrt company in the United states, is firstly marketed in the United kingdom in 1985, and has the following chemical structural formula:
Figure BDA0003527554490000011
given the presence of a chiral center in the structure of etodolac, it is usually administered as a racemic mixture (50: 50). Early chromatographic analysis of etodolac provided only pharmacokinetic data for the racemate and did not reflect the stereoselective pharmacokinetic properties of the different enantiomers. With the establishment of a stereoselective chromatographic separation analysis method, etodolac is found to be a chiral drug, and the study of the document J.Med.chem.,1986,29,871-874 shows that the absolute configuration of racemate with pharmacological activity is S- (+) -etodolac, while R- (-) -etodolac has almost no activity, and the concentrations, apparent distribution volumes, protein combination conditions and metabolism of the two drugs in blood plasma and synovial fluid are greatly different.
At present, the reported methods for synthesizing etodolac racemate are more, but most of the methods are based on various approaches to prepare 7-ethyl tryptophol, then the 7-ethyl tryptophol is cyclized with methyl 3-methoxy-2-pentenoate or methyl 3-oxopentanoate to prepare methyl etodolate, and finally the methyl etodolac is hydrolyzed under alkaline conditions to prepare a target product. The synthetic route is as follows:
Figure BDA0003527554490000012
however, the methods all involve the preparation of etodolac racemate, and the reports on the preparation method of S- (+) -etodolac are few. While current methods for the preparation of S- (+) -etodolac involve chiral resolution strategies, such as US patent 4520203A with cinchonine as the resolving agent and with high yield (45%) and excellent enantiomeric purity (98%) to give S- (+) -etodolac cinchonine salt, which is then isolated as the free enantiomerically pure acid by hydrolysis and extraction of the salt into a suitable solvent. However, this process has limited commercial use due to the use of relatively expensive and toxic alkaloids, and the inefficient extraction, high dilution in methanol to achieve the best product quality. Furthermore, U.S. Pat. No. 3, 4501899A uses cholesteryl aniline for the resolution, U.S. Pat. No. 3, 4544757A uses (+) -borneol for the resolution, and the Organic Process Research & Development,2000,4,418-426 uses N-methylglucamine (meglumine) for the resolution. As is well known, although the chiral resolution technology can separate and remove the R- (-) -etodolac, the S- (+) -etodolac cannot be completely recovered, so that a large amount of raw material medicines are wasted, the yield is lower than 50%, and the production cost is high.
European patent EP0302541A2 discloses a method for synthesizing S- (+) -etodolac, which comprises the steps of taking furan as a starting material, carrying out Friedel-crafts acylation reaction on furan with propionyl halide or propionic anhydride to prepare 1- (furan-2-yl) propane-1-one, then carrying out Reformatsky reaction to generate 3- (furan-2-yl) -3-hydroxyvalerate, carrying out catalytic cyclization by m-chloroperoxybenzoic acid, then reducing to prepare 2- (2-ethyl-3-oxytetrahydro-2H-pyran-2-yl) acetate, carrying out chiral resolution on 2- (2-ethyl-3-oxytetrahydro-2H-pyran-2-yl) acetate, and then cyclizing with o-ethylphenylhydrazine hydrochloride under the protection of nitrogen to prepare S- (+) -etodolac, finally, the S- (+) -etodolac is prepared by sodium hydroxide hydrolysis. The method moves the chiral resolution step forward, and can improve the utilization rate of the substrate and reduce the cost to a certain extent, but the method has the disadvantages of complex operation, long synthesis step, high production cost and limited industrial scale-up production. The synthetic route is as follows:
Figure BDA0003527554490000021
from the above, S- (+) -etodolac methyl ester as a key intermediate for synthesizing S- (+) -etodolac directly affects the production, market supply and quality problems of the drug, and has the following chemical structural formula:
Figure BDA0003527554490000022
in view of the fact that the existing preparation methods of S- (+) -methyl etodolate all prepare single isomers through chiral resolution and have the defects, researches and searches for a chiral synthesis route of S- (+) -methyl etodolate with mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost still needs to be solved at present.
Disclosure of Invention
The invention provides a novel chiral synthesis method of S- (+) -etodolac methyl ester. The method has mild reaction conditions and simple and convenient operation process, and the prepared target product has higher optical purity and yield.
The specific technical scheme of the invention is as follows:
Figure BDA0003527554490000031
wherein X ═ Br, I;
a chiral synthesis method of S- (+) -etodolac methyl ester specifically comprises the following operations:
under the protection of inert gas, dissolving 3-oxo methyl valerate in a reaction solvent A, adding a catalyst and an initial raw material I, stirring at room temperature to react until the raw material I completely reacts, adding alkali into a reaction solution, stirring at controlled temperature to react until the reaction is completely monitored, and performing aftertreatment to obtain S- (+) -methyl etodolate.
Preferably, the reaction solvent a is selected from one of dichloromethane, chloroform, toluene and xylene, preferably dichloromethane.
Preferably, the catalyst includes chiral phosphoric acid catalyst and cinchona alkaloid catalyst, representative examples of catalyst include but are not limited to chiral phosphoric acid catalysts L-1, L-2, L-3 based on BINOL skeleton, and cinchona alkaloid derivatives S-1, S-2, S-3, with S-2 being a more preferred catalyst. The related structural formula is shown as follows:
Figure BDA0003527554490000032
preferably, the base is selected from, but not limited to, one or a combination of sodium methoxide, potassium methoxide, triethylamine, pyridine, DMAP, preferably sodium methoxide.
Preferably, the feeding molar ratio of the starting material I to the methyl 3-oxopentanoate, the catalyst and the base is 1: 1.1-1.4: 5% -15%: 2.25 to 4.0, wherein a ratio of 1: 1.2: 10%: 2.75.
preferably, the temperature control temperature is the reflux temperature of the reaction solvent A.
Preferably, the solvent a is subjected to anhydrous treatment, such as redistillation, molecular sieve treatment, etc., by means of techniques well known to those skilled in the art.
Preferably, the inert gas is selected from inert gases commonly used by those skilled in the art, such as argon, nitrogen, and the like.
Preferably, the method of monitoring the reaction is a reaction monitoring method well known to those skilled in the art, such as thin layer chromatography, liquid chromatography, and the like.
Preferably, in an embodiment, the post-processing step is: cooling the reaction liquid to room temperature, carrying out suction filtration, washing the filter cake by using a reaction solvent A, combining the filtrates, washing the filtrate by using a saturated sodium chloride solution, concentrating the filtrate to be dry, drying, and recrystallizing by using methanol to obtain the target product.
The invention has the beneficial effects that:
the invention provides a chiral synthesis method of S- (+) -etodolac methyl ester, which comprises the following steps: the compound I is used as a starting material and is prepared by catalyzing with 3-oxo methyl valerate through a chiral catalyst. Compared with the method for preparing S- (+) -etodolac methyl ester by chiral resolution technology, the method provided by the invention can prepare a target product with high yield and high purity, and avoids the generation of enantiomer, thereby improving the utilization rate of raw materials and reducing the production cost.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to illustrate the present invention, not to limit the present invention, therefore, the simple modifications of the present invention in the method of the present invention are within the scope of the present invention as claimed.
The invention adopts high performance liquid chromatography to measure the chiral purity of S- (+) -etodolac methyl ester, and the chromatographic conditions are as follows:
and (3) chromatographic column: coated CDMPC columns (20nm, 300mm x 4.0mm. i.d) or columns of comparable performance;
mobile phase: isopropanol-n-hexane (0.39 mol/L);
column temperature: 25 ℃;
detection wavelength: 273 nm;
flow rate: 0.5 ml/min;
sample injection amount: 10 mul;
wherein, the retention time of the S- (+) -etodolac methyl ester is about 9.7min, and the retention time of the chiral isomer is about 14.2 min.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
Under the protection of argon, methyl 3-oxopentanoate (1.56g, 12mmol) was dissolved in dichloromethane (50ml), S-2(0.48g, 1mmol) and starting material I (X ═ Br) (2.52g, 10mmol) were added, the reaction was stirred at room temperature until the reaction of the starting materials was completed, sodium methoxide (1.48g, 27.5mmol) was added to the reaction solution, the reaction was refluxed until the reaction was completed, cooled to room temperature, suction filtered, the cake was washed with dichloromethane, the filtrate was combined, the filtrate was washed with saturated sodium chloride solution (30ml × 3), the filtrate was concentrated to dryness, dried and recrystallized from methanol to obtain the desired product 2.79g, purity 99.3%, and ee% of 99.0%.
Example 2
Under the protection of argon, methyl 3-oxopentanoate (1.43g, 11mmol) was dissolved in dichloromethane (50ml), L-2(0.86g, 1mmol) and starting material I (X ═ Br) (2.52g, 10mmol) were added, the reaction was stirred at room temperature until the reaction of the starting materials was complete, potassium methoxide (1.93g, 27.5mmol) was added to the reaction solution, the reaction was refluxed until the reaction was complete, cooled to room temperature, suction filtered, the filter cake was washed with dichloromethane, the filtrate was combined, the filtrate (30ml × 3) was washed with a saturated sodium chloride solution, the filtrate was concentrated to dryness, dried and recrystallized from methanol to obtain the desired product 2.74g, purity 98.7%, and ee% 98.5%.
Example 3
Under the protection of argon, methyl 3-oxopentanoate (1.36g, 10.5mmol) was dissolved in chloroform (50ml), S-1(0.30g, 1mmol) and starting material I (X ═ Br) (2.51g, 10mmol) were added, the mixture was stirred at room temperature and reacted until the reaction of the starting materials was completed, triethylamine (2.78g, 27.5mmol) was added to the reaction mixture, the reaction was refluxed until the reaction was completed, the reaction mixture was cooled to room temperature, suction filtration was carried out, the cake was washed with chloroform, the filtrates were combined, the filtrate was washed with a saturated sodium chloride solution (30ml × 3), the filtrate was concentrated to dryness, dried and recrystallized with methanol to obtain the objective product of 2.63g, purity 97.5% and ee% of 97.4.
Example 4
Under the protection of argon, methyl 3-oxopentanoate (1.81g, 14mmol) was dissolved in toluene (50ml), L-1(0.35g, 1mmol) and starting material I (X ═ I) (2.99g, 10mmol) were added, the reaction was stirred at room temperature until the starting material reaction was completed, pyridine (2.17g, 27.5mmol) was added to the reaction solution, the reaction was refluxed until the reaction was completed, cooled to room temperature, filtered, the filter cake was washed with toluene, the filtrate was combined, the filtrate was washed with saturated sodium chloride solution (30ml × 3), the filtrate was concentrated to dryness, dried and recrystallized with methanol to obtain the desired product 2.76g, purity 99.1%, and ee% 98.8%.
Example 5
Under the protection of nitrogen, methyl 3-oxopentanoate (1.94g, 15mmol) was dissolved in dichloromethane (50ml), S-2(0.48g, 1mmol) and starting material I (X ═ I) (2.99g, 10mmol) were added, the reaction was stirred at room temperature until the reaction of the starting materials was complete, DMAP (3.36g, 27.5mmol) was added to the reaction mixture, the reaction was refluxed until the reaction was complete, cooled to room temperature, suction filtered, the cake was washed with dichloromethane, the filtrates were combined, the filtrate was washed with saturated sodium chloride solution (30ml × 3), the filtrate was concentrated to dryness, dried and recrystallized from methanol to obtain the desired product 2.67g, purity 98.2%, and ee% was 97.9%.
Example 6
Under the protection of nitrogen, methyl 3-oxopentanoate (1.56g, 12mmol) was dissolved in xylene (50ml), S-2(0.24g, 0.5mmol) and starting material I (X ═ I) (2.99g, 10mmol) were added, the reaction was stirred at room temperature until the reaction of the starting materials was completed, sodium methoxide (1.48g, 27.5mmol) was added to the reaction solution, the reaction was refluxed until completion of the reaction was monitored, cooled to room temperature, suction-filtered, the filter cake was washed with xylene, the filtrates were combined, the filtrate was washed with saturated sodium chloride solution (30ml × 3), the filtrate was concentrated to dryness, dried and recrystallized with methanol to obtain the objective product 2.72g, purity 98.9%, and ee% 98.7%.
Example 7
Under the protection of argon, methyl 3-oxopentanoate (1.56g, 12mmol) was dissolved in dichloromethane (50ml), S-2(0.73g, 1.5mmol), starting material I (X ═ Br) (2.52g, 10mmol) were added, the reaction was stirred at room temperature until the reaction of the starting materials was complete, triethylamine (2.78g, 27.5mmol) was added to the reaction solution, the reaction was refluxed until the reaction was complete, cooled to room temperature, suction filtered, the filter cake was washed with dichloromethane, the filtrates were combined, the filtrate was washed with a saturated sodium chloride solution (30ml × 3), the filtrate was concentrated to dryness, dried and recrystallized from methanol to obtain the desired product 2.78g, purity 99.0%, and ee% 99.0%.
Example 8
Under the protection of nitrogen, methyl 3-oxopentanoate (1.56g, 12mmol) was dissolved in dichloromethane (50ml), S-3(0.42g, 1mmol) and starting material I (X ═ Br) (2.50g, 10mmol) were added, the reaction was stirred at room temperature until the reaction of the starting materials was completed, sodium methoxide (1.22g, 22.5mmol) was added to the reaction solution, the reaction was refluxed until the reaction was completed, cooled to room temperature, suction-filtered, the filter cake was washed with dichloromethane, the filtrate was combined, the filtrate (30ml × 3) was washed with a saturated sodium chloride solution, the filtrate was concentrated to dryness, dried and recrystallized from methanol to obtain the desired product 2.70g, purity 99.2%, and ee% 98.6%.
Example 9
Under the protection of argon, methyl 3-oxopentanoate (1.56g, 12mmol) was dissolved in dichloromethane (50ml), S-3(0.42g, 1mmol) and starting material I (X ═ Br) (2.53g, 10mmol) were added, the reaction was stirred at room temperature until the reaction of the starting materials was completed, sodium methoxide (2.16g, 40mmol) was added to the reaction solution, the reaction was refluxed until the reaction was completed, cooled to room temperature, suction filtered, the filter cake was washed with dichloromethane, the filtrate was combined, the filtrate was washed with a saturated sodium chloride solution (30ml × 3), the filtrate was concentrated to dryness, dried, and recrystallized from methanol to obtain the desired product 2.73g, purity 98.8%, and ee% 98.3%.

Claims (8)

1. A preparation method of S- (+) -methyl etodolate is characterized in that under the protection of inert gas, 3-oxo methyl valerate is dissolved in a reaction solvent A, a catalyst and a starting raw material I are added, stirring reaction is carried out at room temperature until the raw material I completely reacts, alkali is added into a reaction liquid, stirring reaction is carried out at controlled temperature until the reaction is completely monitored, and the S- (+) -methyl etodolate is prepared through aftertreatment, wherein the reaction formula is as follows:
Figure FDA0003527554480000011
wherein X is Br and I.
2. The method according to claim 1, wherein the reaction solvent A is one selected from the group consisting of dichloromethane, chloroform, toluene and xylene.
3. The method of claim 1, wherein the catalyst comprises a chiral phosphoric acid catalyst and a cinchona alkaloid catalyst.
4. The preparation method according to claim 1 or 3, wherein the catalyst is selected from chiral phosphoric acid catalysts L-1, L-2 and L-3 based on BINOL skeleton, and one of cinchona alkaloid derivatives S-1, S-2 and S-3, and the related structural formula is as follows:
Figure FDA0003527554480000012
5. the method according to claim 1, wherein the base is selected from sodium methoxide, potassium methoxide, triethylamine, pyridine, DMAP, or a combination thereof.
6. The preparation method according to claim 1, wherein the molar ratio of the starting material I to the methyl 3-oxopentanoate, the catalyst and the base is 1: 1.1-1.4: 5% -15%: 2.25 to 4.0.
7. The process according to claim 1, wherein the temperature is controlled to the reflux temperature of the reaction solvent A.
8. The method of claim 1, wherein the post-treatment step is: cooling the reaction liquid to room temperature, carrying out suction filtration, washing the filter cake by using a reaction solvent A, combining the filtrates, washing the filtrate by using a saturated sodium chloride solution, concentrating the filtrate until the filtrate is dry, drying, and recrystallizing by using methanol to obtain the target product.
CN202210197229.3A 2021-03-09 2022-03-02 Preparation method of S- (+) -etodolac methyl ester Pending CN115043848A (en)

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